A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, pharmacokinetics, and pharmacodynamics of SB-743921 when administered as a 1-h infusion every 21 days to patients with advanced solid tumors or relapsed/refractory lymphoma.
Patients who failed prior standard therapy or those without any standard options were eligible. Forty-four patients were enrolled using an initial accelerated dose-escalation phase followed by a standard dose-escalation phase. An additional 20 patients were enrolled at the recommended phase II dose to obtain additional safety and pharmacokinetic data. The doses evaluated ranged from 2 to 8 mg/m2. The pharmacokinetics of SB-743921 was evaluated at 19 time-points over 48 h following during administration during cycle 1. Toxicity was assessed by the NCI Common Terminology Criteria version 3.0. Response evaluation was performed every 6 weeks.
The most common and consistent DLT was neutropenia. Other DLTs observed included hypophosphatemia, pulmonary emboli, SVC syndrome, transaminitis, hyponatremia, and hyperbilirubinemia. The MTD of SB-743921 as a 1-h infusion every 21 days was established as 4 mg/m2. The maximum plasma concentration and area under the plasma concentration time curve appeared to increase proportionally to dose. One durable objective response was seen in a patient with metastatic cholangiocarcinoma who was on treatment 11 months and 6 patients had stable disease for over four cycles.
The recommended phase II dose of SB-743921 on this specific schedule of a 1-h infusion every 3 weeks is 4 mg/m2. The promising efficacy and lack of severe toxicities in this study warrant the continued development of SB-743921.
- Dustin, P (1980) Microtubules. Sci Am 243: pp. 66-76 CrossRef
- Wilson, L (1975) Microtubules as drug receptors: pharmacological properties of microtubule protein. Ann N Y Acad Sci 253: pp. 213-231 CrossRef
- Vale, RD, Milligan, RA (2000) The way things move: looking under the hood of molecular motor proteins. Science 288: pp. 88-95 CrossRef
- Burris, HA, Lorusso, P, Jones, S (2004) Phase I trial of novel kinesin spindle protein (KSP) inhibitor SB-715992 IV days 1, 8, 15 q 28 days. J Clin Oncol 22: pp. 2004 CrossRef
- Chu, S, Holen, KD, Rowinsky, EK (2004) Phase I trial of novel kinesin spindle protein (KSP) inhibitor SB-715992 IV Q 21 days. J Clin Oncol 22: pp. 2078 CrossRef
- Stein MN, Tan A, Taber K, Fernandez R, Agrawal NG, Vandendries E, Hsu K, Walker A, Holen K, Wilding G (2007) Phase I clinical and pharmacokinetic (PK) trial of the kinesin spindle protein (KSP) inhibitor MK-0731 in patients with solid tumors. In: 2007 ASCO annual meeting proceedings Part I. J Clin Oncol 25(18S):2007 (June 20 Supplement; abstr 2548)
- Infante JR, Spratlin JL, Kurzrock R, Eckhardt SG, Burris HA, Puchalski TA, Li J, Wu K, Ochs J, Herbst RS (2008) Clinical, pharmacokinetic (PK), pharmacodynamic findings in a phase I trial of weekly (wkly) intravenous AZD4877 in patients with refractory solid tumors. J Clin Oncol 26:2008 (May 20 suppl; abstr 2501)
- Stephenson JJ, Lewis N, Martin JC, Ho A, Li J, Wu K, Pace L, Eder JP, Schwartz GK (2008) Phase I multicenter study to assess the safety, tolerability, and pharmacokinetics of AZD4877 administered twice weekly in adult patients with advanced solid malignancies. J Clin Oncol 26:2008 (May 20 suppl; abstr 2516)
- A first in human study of SB-743921, a kinesin spindle protein inhibitor, to determine pharmacokinetics, biologic effects and establish a recommended phase II dose
Cancer Chemotherapy and Pharmacology
Volume 67, Issue 2 , pp 447-454
- Cover Date
- Print ISSN
- Online ISSN
- Additional Links
- Phase I
- Kinesin spindle protein
- Industry Sectors
- Author Affiliations
- 1. University of Wisconsin Carbone Cancer Center, K4/528, 600 Highland Ave., Madison, WI, 53792-5666, USA
- 2. University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
- 3. GlaxoSmithKline R&D, Research Triangle Park, NC, USA
- 4. GlaxoSmithKline R&D, Collegeville, USA